ClinVar Genomic variation as it relates to human health

The c.2344A>G missense variant has been identified in individuals with breast cancer and pancreatic cancer (Easton 2016, Shindo 2017), but has not to our knowledge been reported in an individual with ovarian cancer. The vast majority of pathogenic variants reported in the BRIP1 gene to date are truncating variants. The c.2344A>G variant has an allele frequency of 0.000008 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk.

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Easton 2016, Shindo 2017); Published functional studies are inconclusive: lack of cisplatin sensitivity but intermediate mitomycin C sensitivity (Moyer 2020); This variant is associated with the following publications: (PMID: 24123366, 26921362, 28767289, 27535533, 31822495)

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

The frequency of this variant in the general population, 0.000008 (2/251332 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer and in controls (PMID: 26921362 (2016)) as well as in individuals affected with pancreatic cancer (PMID: 28767289 (2017)). One functional study described this variant as a hypomorph due to the modest reduction in cellular growth observed after high-dose treatment with a DNA damaging agent (PMID: 31822495 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: BRIP1 c.2344A>G (p.Ile782Val) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2344A>G has been reported in the literature, primarily as a VUS in settings of multigene panel testing, in individuals affected with pancreatic, breast, and ovarian cancers, and also in at least one control individual (e.g. Easton_2016, Shindo_2017, Moyer_2020, Bhai_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A functional study evaluated the effect of the variant using a transient DNA damage-based rescue assay and categorized the variant as hypomorphic (Moyer_2020); however, this does not allow strong conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31822495, 28767289, 26921362). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces isoleucine with valine at codon 782 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant resulted in hymomorphic activity in a mitomycin C sensitivity assay (PMID: 31822495). This variant has been detected in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and in 10/101759 breast cancer and 1/15587 ovarian cancer cases (PMID: 31822495). This variant also has been reported in the general population (PMID: 31822495) and in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/17-59820409-T-C). A breast cancer case-control meta-study has been detected this variant in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000419). This variant has been identified in 2/251332 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 782 of the BRIP1 protein (p.Ile782Val). This variant is present in population databases (rs142806416, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 26921362, 28767289, 34326862). ClinVar contains an entry for this variant (Variation ID: 142346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRIP1 function (PMID: 31822495). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.I782V variant (also known as c.2344A>G), located in coding exon 15 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2344. The isoleucine at codon 782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast, pancreatic, and ovarian cancer patients, as well as in a control (Easton DF et al. J Med Genet, 2016 05;53:298-309; Shindo K et al. J. Clin Oncol, 2017 Oct;35:3382-3390; Moyer CL et al. Cancer Res, 2020 02;80:857-867). In an inter-strand cross link damage survival assay, the p.I782V alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res, 2020 02;80:857-867). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.